During the past five years of this grant, a previously-unsuspected mechanism of granulocyte (PMN)-induced tissue damage was uncovered--that is, PMNs were shown to aggregate and then embolize when exposed to a single activated complement (C) component, C5a. Moreover, C5a-exposed PMNs were also demonstrated to become cytotoxic for endothelial cells in vitro and in vivo (viewed as plasma leak from the rat mesenteric vasculature). We now plan to examine in detail the molecular basis for PMN aggregation and endothelial cytotoxicity, particularly concentrating on arachidonate and oxygen-radical metabolism of C5a exposed PMNs. In parallel, the possible relevance of C5a-induced PMN stimulation in aggravating tissue damage in three clinical syndromes will be sought--that of myocardial infarction, burns, and hemorrhagic pancreatitis. It is proposed: (a) that C-generated PMN aggregates form in patent vessels and extend myocardial infarct damage, and that similar aggregates also promote extravasation of blood into inflamed pancreatic tissue; and (b) that C5a-stimulation of PMNs produces generalized vascular endothelial damage in burns, producing thereby plasma loss remote from traumatized tissues.